Click chemistry, particularly the copper(I)-catalyzed azide alkyne cycloaddition (CuAAC), has found applications in a wide range of modern chemistry-related areas, including organic chemistry, drug discovery, drug delivery and chemical biology. However, the toxicity of copper(I) from the generation of reactive nitrogen and oxygen species limits its application in living systems. For example, upon treatment of 1 mM CuSO4, 1.5 mM sodium ascorbate, and 0.1 mM TBTA, Zebrafish embryos do not survive beyond 15 min. Therefore, the removal of copper species is typically required in order to avoid cytotoxicity caused by residual copper ions in biological applications, adding another layer of complexity to the application of CuAAC in living systems. To overcome the cumbersome copper removal problem, major efforts have been made to minimize the risk caused by this metal catalyst. New methodologies and techniques have been developed, including copper-free variants of azide-alkyne click chemistry (e.g., strain-promoted azide-alkyne cycloaddition (SPPAC) and resin-supported catalyst systems). However, these strategies cannot fulfill all the requirements due to their inherent deficiencies, including relatively sluggish kinetics in SPAAC and copper leaching problems observed in the resin-supported catalyst systems. Therefore, a more efficient approach is highly desired.